Malaria is a disease of global importance. 300 million people are infected annually and over 2 million succumb to the disease. Most of these are women and children. While many people are infected by the identical strain of the parasite P. falciparum not everyone responds in the same manner. Some people develop mild symptoms and go on to develop immunity to the clinical signs and symptoms of disease. Others develop a severe clinical syndrome which can rapidly end in death through either cerebral malaria or a severe anemia. It is highly likely that a major factor in the outcome to disease is the host response to infection. This is especially the case in the murine model of malaria, P. chabaudi the major determinant of outcome is genetic. Some strains of mouse control the level at which their red cells are infected and hence are able to survive and infection. Some strains of mouse also mount a more vigorous immune response to clear parasites from the circulation. The underlying biology of these phenomena is not understood. The purpose of this application is to understand why some strains of mouse are more able to survive a malarial infection than others. While the model used is different to falciparum malaria in humans, the questions are sufficiently basic to apply to most malarial infections. Three loci-controlling outcome to infection have been identified in the mouse. These are on chromosomes 8,.9 and 17. This project aims to identify the genes underlying these loci. Congenic animals will be used to fine map the loci. Physical maps will be used to clone the region in BACs. These BACs will be injected into animal as transgenes and these animals tested for a change in phenotype. In such animals where the BACs have complemented the phenotve, fragmented BACs will further narrow to the region to one containing only one gene. The biology of these loci will be studied in congenic animals. This will give the physiological correlates of the resistance phenotype seen in these mouse strains. It may also help in the cloning of the responsible genes. The study of natural genetic variants has limitations in the number of genes found and in the ease of identifying such genes. Therefore a program of finding new genes important in the host response to malaria will be undertaken using an ENU mutagenesis protocol. Susceptible, mutated mice will be challenged with parasites and those surviving infection will be further studied. The outcome of this project should be the description of new pathways involved in host response to malaria.